Use of therapeutic human albumin for the preparation of a drug for the treatment of patients suffering from cognitive disorders

This application claims the benefit of priority to Spanish Patent Application No. P200702831 filed Oct. 26, 2007, the disclosure of which is hereby incorporated by reference in its entirety.

The present invention relates to the use of therapeutic human albumin for the preparation of a drug for the treatment of cognitive disorders such as Alzheimer\'s disease. The drug will preferably be for administration to the patient by plasma exchange (therapeutic plasmaphaeresis). At the same time, the present invention will provide the means for the treatment of cognitive disorders in individuals suffering from Alzheimer\'s disease or of those who are suspected of being suffering from this disease.

The invention is the result of the investigations performed by the inventor, which have resulted in a new use of human therapeutic albumin for treatment preferably by therapeutic plasma exchange which has proved to be effective in the treatment of Alzheimer\'s disease.

Alzheimer\'s disease is an irreversible cerebral degenerative pathology which affects the nerve cells of the cerebral cortex in a diffuse fashion, and also other adjacent structures such as the Hippocampus. This causes the deterioration of the subject\'s capacity to control emotions, recognise errors and patterns of behaviour and coordinate movements and memory, which combined are known as dementia. Finally the memory and the higher mental faculties are completely lost.

The hippocampus is a region of the brain situated in the temporal lobe which extends along the whole of the lower part of the inferior horn of the lateral ventricles (it measures about 5 cm). It takes its name from the shape of a “sea horse” which its folds take in the transverse sections of the brain. The hippocampus is formed principally of neurones of the grey matter although it has a thin layer of white matter on the upper surface connected to the lateral ventricles.

Functionally, the hippocampus forms one of the most prominent parts of the limbic system, which plays a preponderant role in the control of the higher functions, especially the emotions [Purves D, Augustine G J, Fitzpatrick D, Katz L C, LaMantia A, McNamara J O and Williams S M, in: Neuroscience. Sunderland (MA). Sinauer Associates, Inc.; c2001].

It is at present considered that the hippocampus is one of the most intensely affected cerebral regions in Alzheimer\'s disease (loss of volume) and several reports suggest that the loss of hippocampus neurones is correlated to the loss of memory which is observed in this disease [Rössler M, Zarski R, Bohl J. and Ohm TG. Stage-dependent and sector-specific neuronal loss in hippocampus during Alzheimer\'s disease. Acta Neuropatol (2002) 103:363-369].

In Alzheimer\'s disease specific changes also occur in the cerebral structures, amongst which is a tangling of the neuron fibrils, known as neurofibrillar bundles, and an extracellular protein deposit in the form of the so-called beta-amyloid (Aβ) peptide plaque. These neurofibrillar bundles and beta amyloid plaques have been connected with the development of the disease. In spite of this the cause of the disease is unknown, although the commonly accepted theory associates the development of the disease with a deposition of the beta-amyloid (Aβ) peptide.

The neurofibrillar bundles contain, inter alia, residues of damaged microtubules, and these microtubules form a structure allowing the flow of nutrients through the neuron. A fundamental component of these bundles is the aberrant form of the so-called tau protein, which in its “normal” form contributes to the formation of a suitable structure of microtubules. Instead, an anomalous tau protein blocks the action of a healthy tau protein. Aβ is a protein which accumulates in the form of neuritic plaques which appear surrounded by the residues of destroyed ramifications of the affected neurons. Aβ is in turn a fragment of the so-called amyloid precursor protein (APP) which upon being cut by determined enzymes can give rise to different types of Aβ, hence this protein has a certain heterogeneity in its sequence of amino acids, the Aβ40 form being the most common in normal subjects. The Aβ42 (“long Aβ”) form shows a greater tendency to aggregate, and there is a theory which suggests that it could be responsible for initiating aggregation into plaques.

High Aβ levels in the Cerebrospinal Fluid (CSF) are associated with low levels of acetylcholine, which is an important neurotransmitter, or chemical messenger which transmits signals between the cerebral neurons. Acetylcholine forms part of the cholinergic system, vital for memory and learning, which is progressively destroyed in Alzheimer\'s disease patients.

As in this disease a strong synaptic loss and a profound change in the cholinergic and glutamatergic neurotransmitter systems occur, and the current treatment attempts to mitigate the synaptic pathology with the drugs today in use, the anticholinesterasics and NMDA glutamatergic antagonists. These cholinergic and antiglutamatergic drugs could retain their indication for the future because, as this disease is so molecularly complex, adjusted polytherapy can be necessary in each developing stage in which the process is encountered.

In addition, the current investigation is fundamentally centred on drugs which try to halt the progression of the disease from the start. Antiamyloid agents are used, which effectively impede the excessive production of Aβ, its aggregation and deposit or which clean accumulations of Aβ once they have been formed. Another important target is the agents which avoid phosphorylation and aggregation of tau so as not to form bundles.

There are at present several drugs which are already under clinical trial following these routes of activation, with agents which try to inhibit the formation of APP, as indicated for example in the EP1576955 patent.

Another strategy at present under trial is the use of certain anti-inflammatories, such as flurbiprofen, described in the WO2005065069 patent, which acts by modulating γ-secretase activity.

The option of inhibiting γ-secretase is compromised because this enzyme has many other substrata which, if they are also inhibited, can produce side effects.

Another therapeutic possibility which is at present being studied is that of avoiding the conversion of the soluble Aβ into insoluble restructures which form deposits, such as the drug Alzhemed of the Canadian company Neurochem, which opposes the fibrilisation of Aβ, inhibiting its deposit.

Moreover, the Aβ does not aggregate spontaneously but depends on metals such as Cu, Fe and Zn. These metals increase in the brain in cases of Alzheimer\'s disease triggering the precipitation of Aβ. The chelating compounds which combine with these metals can correct the aggregation of Aβ and be of therapeutic use in the treatment of Alzheimer\'s disease, as described in the WO2004031161 document.

The anti-Aβ immunotherapy originated when it was discovered that areas of inflammation appeared around the Aβ deposits and neurofibrillar bundles, in response to these abnormal structures. This gave rise to clinical studies with vaccines based on synthetic Aβ, which even if they acted against the accumulation of Aβ, caused severe side effects, such as the development of serious meningoencephalitis resulting in death in some cases. At present safer and more efficacious agents are being sought.

These mechanisms of action are principally based on blocking the formation of the insoluble form of Aβ, avoiding its deposit or the elimination of the deposits already formed, all of them acting directly on the cerebral tissue. This involves, as we have remarked, a risk of adverse side effects by direct action on the central nervous system.

Another aspect considered in the therapeutic strategy against Alzheimer\'s disease is, bearing in mind that the production of Aβ is continuous in the brain, its accumulation due to the deficient transfer of the CSF to the blood and the elimination of this could increase the possibility of the deposition of this Aβ in the brain.

Following this line of activity, US 2005/0239062 refers to the therapeutic activity of increasing the transport of the Aβ across the Haematoencephalic Barrier (a mechanism which seems not to function correctly in Alzheimer\'s disease), acting at the level of specific transporters of this Aβ.